According to the thymus selection theory, the capacity of T cells to recognize antigen in association with a particular set of H-2 determinants requires that the T cells encounter these determinants in the thymus during ontogeny. Although much evidence is in favor of this hypothesis, there are increasing numbers of reports that T cells can show restriction to H-2 determinants not encountered in the thymus. Such restriction might signify that the role of the thymus in dictating H-2 restriction is not absolute, i.e., that the system is leaky. The opposing viewpoint is that the numerous examples of restriction to nonthymic H-2 determinants all reflect experimental artifacts of one sort or another. In this research, concerted efforts will be made to attempt to discriminate between these two possibilities. Although confrontation with H-2 determinants in the thymus clearly influences T-cell responsiveness to conventional antigens, the question of whether the thymus controls the development of alloreactivity is poorly understood. Direct evidence will be sought on whether the thymus does indeed influence alloreactivity. Bone marrow transplantation in mice using H-2-compatible strain combinations can lead to lethal graft-versus-host disease (GVHD); multiple minor histocompatibility antigens (minor HA) appear to be the main target for GVHD. This research will study the immunobiology of GVHD to minor HA. The information from such studies might pertain to the syndrome of GVHD commonly seen in humana after HLA-compatible bone marrow transplantation. During the last year, we have concentrated on defining which particular T cells are involved in eliciting graft-versus-host disease (GVHD) to minor versus major histocompatibility differences in mice. The results show that T cells evoking lethal GVHD to minor H differences or allo Class I differences have the phenotype Lyt 1-L3T4-Lyt 2+. In the case of GVHD to allo Class II differences, Lyt 1+L3T4+Lyt 2-T cells appear to be the main effector cells, although Lyt 1-L3T4-Lyt 2+ might also play a role. Whether the two types of T cells induce qualitatively different forms of GVHD is currently under investigation. (TT)